EA035350B1 - ЦИКЛИЧЕСКИЕ ЭФИРНЫЕ ПРОИЗВОДНЫЕ ПИРАЗОЛО[1,5-а]ПИРИМИДИН-3-КАРБОКСАМИДА - Google Patents

ЦИКЛИЧЕСКИЕ ЭФИРНЫЕ ПРОИЗВОДНЫЕ ПИРАЗОЛО[1,5-а]ПИРИМИДИН-3-КАРБОКСАМИДА Download PDF

Info

Publication number: EA035350B1
Authority: EA; Eurasian Patent Office
Prior art keywords: group; compound; formula; alkyl; mmol
Prior art date: 2015-10-13

Application number

EA201890922A

Other languages

English (en)

Russian (ru)

Other versions

EA201890922A1 (ru

Inventor

Кристоф Хёнке

Барбара Бертани

Марко Феррара

Джакомо Фоссати

Сара Фраттини

Риккардо Джованнини

Скотт Хобсон

Original Assignee

Бёрингер Ингельхайм Интернациональ Гмбх

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2015-10-13

Filing date

2016-10-12

Publication date

2020-05-29

2016-10-12 Application filed by Бёрингер Ингельхайм Интернациональ Гмбх filed Critical Бёрингер Ингельхайм Интернациональ Гмбх

2018-11-30 Publication of EA201890922A1 publication Critical patent/EA201890922A1/ru

2020-05-29 Publication of EA035350B1 publication Critical patent/EA035350B1/ru

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-1 CYCLIC ETHER DERIVATIVES OF PYRAZOLO[1,5-a]PYRIMIDINE-3-CARBOXYAMIDE Chemical class 0.000 title description 32
150000001875 compounds Chemical class 0.000 claims abstract description 212
101001098814 Dictyostelium discoideum 3',5'-cyclic-nucleotide phosphodiesterase regA Proteins 0.000 claims abstract description 33
239000003112 inhibitor Substances 0.000 claims abstract description 19
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
150000003839 salts Chemical class 0.000 claims description 58
125000000217 alkyl group Chemical group 0.000 claims description 39
125000001424 substituent group Chemical group 0.000 claims description 33
229910052736 halogen Inorganic materials 0.000 claims description 25
150000002367 halogens Chemical class 0.000 claims description 24
125000003118 aryl group Chemical group 0.000 claims description 21
125000001072 heteroaryl group Chemical group 0.000 claims description 19
230000000694 effects Effects 0.000 claims description 13
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
239000003814 drug Substances 0.000 claims description 10
125000004076 pyridyl group Chemical group 0.000 claims description 10
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
229920006395 saturated elastomer Polymers 0.000 claims description 8
125000005842 heteroatom Chemical group 0.000 claims description 6
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
125000004432 carbon atom Chemical group C* 0.000 claims description 5
229910052717 sulfur Inorganic materials 0.000 claims description 4
125000005843 halogen group Chemical group 0.000 claims description 3
125000002950 monocyclic group Chemical group 0.000 claims description 3
229910052760 oxygen Inorganic materials 0.000 claims description 3
125000006413 ring segment Chemical group 0.000 claims description 3
125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims 1
230000002401 inhibitory effect Effects 0.000 claims 1
238000000034 method Methods 0.000 abstract description 218
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 30
201000010099 disease Diseases 0.000 abstract description 16
230000008569 process Effects 0.000 abstract description 4
208000015114 central nervous system disease Diseases 0.000 abstract description 2
238000004519 manufacturing process Methods 0.000 abstract description 2
150000002170 ethers Chemical class 0.000 abstract 1
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 145
239000000203 mixture Substances 0.000 description 124
239000000543 intermediate Substances 0.000 description 115
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 64
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 57
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
239000000243 solution Substances 0.000 description 47
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 46
239000003480 eluent Substances 0.000 description 40
239000002904 solvent Substances 0.000 description 32
150000001414 amino alcohols Chemical class 0.000 description 31
239000011541 reaction mixture Substances 0.000 description 31
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
238000000746 purification Methods 0.000 description 30
IXLVUUFUDRJUSL-RPBOFIJWSA-N 5-[[4-(3-acetamidophenyl)phenyl]methyl]-n-[(1s,2r)-2-phenylcyclopropyl]-1,3-oxazole-4-carboxamide Chemical compound CC(=O)NC1=CC=CC(C=2C=CC(CC3=C(N=CO3)C(=O)N[C@@H]3[C@H](C3)C=3C=CC=CC=3)=CC=2)=C1 IXLVUUFUDRJUSL-RPBOFIJWSA-N 0.000 description 27
206010012289 Dementia Diseases 0.000 description 27
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
238000011282 treatment Methods 0.000 description 25
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 23
230000002378 acidificating effect Effects 0.000 description 21
210000001175 cerebrospinal fluid Anatomy 0.000 description 21
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
238000003818 flash chromatography Methods 0.000 description 20
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
239000012043 crude product Substances 0.000 description 19
210000002381 plasma Anatomy 0.000 description 19
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
229910052938 sodium sulfate Inorganic materials 0.000 description 18
235000011152 sodium sulphate Nutrition 0.000 description 18
238000002360 preparation method Methods 0.000 description 17
208000028698 Cognitive impairment Diseases 0.000 description 16
208000010877 cognitive disease Diseases 0.000 description 16
235000019439 ethyl acetate Nutrition 0.000 description 16
239000012071 phase Substances 0.000 description 16
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
239000002253 acid Substances 0.000 description 15
230000035699 permeability Effects 0.000 description 15
208000024827 Alzheimer disease Diseases 0.000 description 14
238000001514 detection method Methods 0.000 description 14
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210000004556 brain Anatomy 0.000 description 13
239000000460 chlorine Substances 0.000 description 13
239000007787 solid Substances 0.000 description 13
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210000004027 cell Anatomy 0.000 description 12
238000006243 chemical reaction Methods 0.000 description 12
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102000004506 Blood Proteins Human genes 0.000 description 11
108010017384 Blood Proteins Proteins 0.000 description 11
238000004296 chiral HPLC Methods 0.000 description 11
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
238000004458 analytical method Methods 0.000 description 10
KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 10
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
229910000041 hydrogen chloride Inorganic materials 0.000 description 10
KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 10
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 9
150000001412 amines Chemical class 0.000 description 9
210000003169 central nervous system Anatomy 0.000 description 9
ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
229940079593 drug Drugs 0.000 description 9
238000004128 high performance liquid chromatography Methods 0.000 description 9
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
239000013543 active substance Substances 0.000 description 8
239000000872 buffer Substances 0.000 description 8
239000012634 fragment Substances 0.000 description 8
230000002503 metabolic effect Effects 0.000 description 8
239000012044 organic layer Substances 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
150000003254 radicals Chemical class 0.000 description 8
201000000980 schizophrenia Diseases 0.000 description 8
238000012360 testing method Methods 0.000 description 8
ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 7
102000004190 Enzymes Human genes 0.000 description 7
108090000790 Enzymes Proteins 0.000 description 7
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
230000009056 active transport Effects 0.000 description 7
229940088598 enzyme Drugs 0.000 description 7
229910052731 fluorine Inorganic materials 0.000 description 7
150000002500 ions Chemical class 0.000 description 7
239000012074 organic phase Substances 0.000 description 7
241000700159 Rattus Species 0.000 description 6
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
230000003542 behavioural effect Effects 0.000 description 6
229910052794 bromium Inorganic materials 0.000 description 6
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
235000019441 ethanol Nutrition 0.000 description 6
229910052739 hydrogen Inorganic materials 0.000 description 6
230000001771 impaired effect Effects 0.000 description 6
238000000338 in vitro Methods 0.000 description 6
238000011534 incubation Methods 0.000 description 6
230000005764 inhibitory process Effects 0.000 description 6
239000003643 water by type Substances 0.000 description 6
XCTQZIUCYJVRLJ-UHFFFAOYSA-N 1-bromo-2-fluoro-4-(trifluoromethyl)benzene Chemical compound FC1=CC(C(F)(F)F)=CC=C1Br XCTQZIUCYJVRLJ-UHFFFAOYSA-N 0.000 description 5
208000019901 Anxiety disease Diseases 0.000 description 5
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
229940121828 Phosphodiesterase 2 inhibitor Drugs 0.000 description 5
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
235000019270 ammonium chloride Nutrition 0.000 description 5
229910052801 chlorine Inorganic materials 0.000 description 5
AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 5
238000000502 dialysis Methods 0.000 description 5
239000012528 membrane Substances 0.000 description 5
230000036470 plasma concentration Effects 0.000 description 5
239000011734 sodium Substances 0.000 description 5
230000032258 transport Effects 0.000 description 5
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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239000007821 HATU Substances 0.000 description 4
229940121948 Muscarinic receptor antagonist Drugs 0.000 description 4
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
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UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 4
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DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
239000011701 zinc Substances 0.000 description 4
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XTYLJMKJLMHFJK-UHFFFAOYSA-N 1,1,3,3-tetraethoxy-2-methylpropane Chemical compound CCOC(OCC)C(C)C(OCC)OCC XTYLJMKJLMHFJK-UHFFFAOYSA-N 0.000 description 3
JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 3
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HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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EA201890922A 2015-10-13 2016-10-12 ЦИКЛИЧЕСКИЕ ЭФИРНЫЕ ПРОИЗВОДНЫЕ ПИРАЗОЛО[1,5-а]ПИРИМИДИН-3-КАРБОКСАМИДА EA035350B1 (ru)

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Application Number	Priority Date	Filing Date	Title
EP15189600.8A EP3156405A1 (fr)	2015-10-13	2015-10-13	Dérivés d'éther spirocycliques de pyrazolo [1,5-a] pyrimidine-3-carboxamide
PCT/EP2016/074380 WO2017064082A1 (fr)	2015-10-13	2016-10-12	Dérivés d'éther cyclique de pyrazolo[1,5-a]pyrimidine-3-carboxyamide

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EA201890922A1 EA201890922A1 (ru)	2018-11-30
EA035350B1 true EA035350B1 (ru)	2020-05-29

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US (5)	US10023575B2 (fr)
EP (2)	EP3156405A1 (fr)
JP (1)	JP6626965B2 (fr)
KR (1)	KR102611558B1 (fr)
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AU (1)	AU2016338602B2 (fr)
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CL (1)	CL2018000856A1 (fr)
CO (1)	CO2018003756A2 (fr)
CY (1)	CY1125323T1 (fr)
DK (1)	DK3362453T3 (fr)
EA (1)	EA035350B1 (fr)
ES (1)	ES2912223T3 (fr)
HR (1)	HRP20220595T1 (fr)
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LT (1)	LT3362453T (fr)
MA (1)	MA42988B1 (fr)
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MY (1)	MY195169A (fr)
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PE (2)	PE20190778A1 (fr)
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SI (1)	SI3362453T1 (fr)
UA (1)	UA124576C2 (fr)
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EP3156405A1 (fr) *	2015-10-13	2017-04-19	Boehringer Ingelheim International GmbH	Dérivés d'éther spirocycliques de pyrazolo [1,5-a] pyrimidine-3-carboxamide
RU2671964C1 (ru) *	2017-08-30	2018-11-08	Сиа Эволед	Пиразоло[1,5-а]пиримидинкарбоксилаты гадолиния и органические светодиоды на их основе
TWI745836B (zh) *	2019-01-18	2021-11-11	大陸商蘇州亞盛藥業有限公司	作為mcl-1抑製劑的大螺環醚
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US10875867B2 (en)	2020-12-29
US10023575B2 (en)	2018-07-17
US12351584B2 (en)	2025-07-08
JP6626965B2 (ja)	2019-12-25
PH12018500796A1 (en)	2018-10-29
WO2017064082A1 (fr)	2017-04-20
US10479794B2 (en)	2019-11-19
IL258070B (en)	2020-06-30
RS63218B1 (sr)	2022-06-30
US20170101411A1 (en)	2017-04-13
LT3362453T (lt)	2022-05-25
KR20180063316A (ko)	2018-06-11
BR112018004347A2 (pt)	2018-10-09
EP3362453A1 (fr)	2018-08-22
CA3001929C (fr)	2023-11-28
MX376458B (es)	2025-03-07
US20230286993A1 (en)	2023-09-14
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CN114181213B (zh)	2024-08-30
IL258070A (en)	2018-05-31
CN114181213A (zh)	2022-03-15
PE20181447A1 (es)	2018-09-12
PL3362453T3 (pl)	2022-07-25
ES2912223T3 (es)	2022-05-25
EP3156405A1 (fr)	2017-04-19
CO2018003756A2 (es)	2018-07-10
US20180134720A1 (en)	2018-05-17
CA3001929A1 (fr)	2017-04-20
EA201890922A1 (ru)	2018-11-30
MA42988B1 (fr)	2022-04-29
MX2018004524A (es)	2018-06-27
PE20190778A1 (es)	2019-06-06
UA124576C2 (uk)	2021-10-13
CN108137602B (zh)	2021-09-28
PH12018500796B1 (en)	2022-10-26
HRP20220595T1 (hr)	2022-06-10
AU2016338602A1 (en)	2018-03-15
SI3362453T1 (sl)	2022-06-30
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CN108137602A (zh)	2018-06-08
MY195169A (en)	2023-01-11
CL2018000856A1 (es)	2018-07-27
KR102611558B1 (ko)	2023-12-11
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US20210032259A1 (en)	2021-02-04
HK1254651A1 (en)	2019-07-26
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US11691977B2 (en)	2023-07-04
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CN104725359B (zh)	2017-05-03	取代的哌嗪化合物及其使用方法和用途
AU2017353313C1 (en)	2022-06-09	(1,2,4)triazolo(1,5-a)pyrimidine compounds as PDE2 inhibitors
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US9416143B2 (en)	2016-08-16	Griseofulvin derivatives
EA029313B1 (ru)	2018-03-30	Производные пиперазина и их применение в качестве лекарственного средства
US9006226B2 (en)	2015-04-14	Dihydropteridinones I
JP6052527B2 (ja)	2016-12-27	ジヒドロプテリジノンｉ
RU2666728C2 (ru)	2018-09-12	Трициклические триазольные соединения
HK1254651B (en)	2022-10-28	Cyclic ether derivatives of pyrazolo[1,5-a]pyrimidine-3-carboxyamide